The classification and nomenclature of phencyclidine and sigma receptor sites have been reviewed (Trends Neuroscience 1987; 10:444 446 and Clin. Neuropharmacol. 1988; 11:105). The structural determinants of sigma receptor affinity have been described (Mol. Pharmacol. 1987; 32:772 784). The compounds of the present invention have been found to have high affinity for the sigma site.
Sigma binding sites are found in the brain (J. M. Walker, et al, Pharmacol. Rev. 1990; 42:355) and have been implicated in a number of disease states such as psychosis and various motor disorders (dystonias and dyskinesia). For example, the mode of action of the potential antipsychotic rimcazole and BMY 14802 is believed to be related in part to an interaction through sigma sites (D. P. Taylor, et al, Drug Dev. Res. 1987; 11:65). However, controversy exists as to the actual role of sigma sites in antipsychotic drug action (K. L. R. Jansen, Clin. Neuropharm. 1988; 11:565). High concentrations of sigma receptors are found in the red nucleus (RN), an area involved in posture and movement. It is reported that microinjection of sigma ligands to the RN of rats causes abnormal postural changes (dystonias) (J. M. Walker, et al, Neurology 1988; 38:961). Abnormal sigma binding patterns have been observed in brain from genetically dystonic rats (W. D. Bowen, et al, Eur. J. Pharmacol. 1988; 147:153). Also, certain steroids are naturally occurring ligands for the sigma binding site (T. Su, et al, Science 1988; 240:219), which raises the possibility that the sigma site may mediate some aspects of steroid-induced mental disturbances and alterations in immune functions. Further, sigma binding sites are found in spleen and lymphocytes (T. Su, et al, Eur. J. Pharmacol. 1988; 148:467 and S. A. Wolfe, et al, Soc. Neurosci. Abstr. 1987; 13:1437), suggesting that sigma binding sites may play an important role in the immune system.
Since the sigma binding site was first postulated in 1976 (W. R. Martin, et al, J. Pharmacol. Exp. Ther. 1976; 197:517), a great number of studies have been carried out to discover its nature and function (J. M. Walker, Pharmacol. Rev. 1990; 42:355). Despite the considerable amount of work, there are no known commercially available agonists or antagonists for the sigma binding sites. DuP 734, [1-(cyclopropylmethyl)-4-(2',4"-fluoroethyl) 2'-oxoethyl)piperidine HBr] which has antipsychotic properties, is believed to be a sigma binding site antagonist (L. Cook, et al, Abstract 133.8, p. 333, Society for Neuroscience, 21st Annual Meeting, New Orleans, La., November 10-15, 1991). The availability of selective sigma ligands is highly desirable as tools to further unravel the biological and pharmacological role played by sigma sites.